Liver enzyme abnormalities in coronavirus 2019 (COVID-19) are being addressed in the literature. The predictive risk of elevated liver enzymes has not been established for COVID-19 mortality. In this study, we hypothesized that elevated liver enzymes at admission can predict the outcome of COVID-19 disease with other known indicators, such as comorbidities.

This retrospective study included all the consecutive hospitalized patients with confirmed COVID-19 disease from March 4th to May 31st, 2020. The study was conducted in Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, India. We assessed demography, clinical variables, COVID-19 severity, laboratory parameters, and outcome.

We included 1,512 patients, and median age was 47 years (interquartile range: 34–60) with 36.9% being female. Liver enzyme level (aspartate aminotransferase and/or alanine aminotransferase) was elevated in 450/1,512 (29.76%) patients. Comorbidity was present in 713/1,512 (47.16%) patients. Patients with liver enzymes’ elevation and presence of comorbidity were older, more frequently hospitalized in ICU and had more severe symptoms of COVID-19 at the time of admission. Presence of liver enzymes’ elevation with comorbidity was a high risk factor for death (OR: 5.314, 95% CI: 2.278–12.393), as compared to patients with presence of comorbidity (OR: 4.096, 95% CI: 1.833–9.157).

Comorbidity combined with liver enzymes’ elevation at presentation independently increased the risk of death in COVID-19 by at least 5-fold.

The liver is frequently affected by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. The most common manifestations are mildly elevated alanine aminotransferase and aspartate aminotransferase, with a prevalence of 16-53% among patients. Cases with severe coronavirus disease 2019 (COVID-19) seem to have higher rates of acute liver dysfunction, and the presence of abnormal liver tests at admission signifies a higher risk of severe disease during hospitalization. Patients with chronic liver diseases also have a higher risk of severe disease and mortality (mainly seen in patients with metabolic-associated fatty liver disease). Several pathways of damage have been proposed in the liver involvement of COVID-19 patients; although, the end-cause is most likely multifactorial. Abnormal liver tests have been attributed to the expression of angiotensin-converting enzyme 2 receptors in SARS-CoV-2 infection. This enzyme is expressed widely in cholangiocytes and less in hepatocytes. Other factors attributed to liver damage include drug-induced liver injury, uncontrolled release of proinflammatory molecules (“cytokine storm”), pneumonia-associated hypoxia, and direct damage by the infection. Hepatic steatosis, vascular thrombosis, fibrosis, and inflammatory features (including Kupffer cell hyperplasia) are the most common liver histopathological findings in deceased COVID-19 patients, suggesting important indirect mechanisms of liver damage. In this translational medicine-based narrative review, we summarize the current data on the possible indirect mechanisms involved in liver damage due to COVID-19, the histopathological findings, and the impact of these mechanisms in patients with chronic liver disease.

With an increasing understanding of hepatitis B, the antiviral indications have been broadening gradually. To evaluate the effectiveness of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and detectable hepatitis B virus (HBV) DNA, those who are ineligible for broader antiviral criteria from the Chinese CHB prevention guide (2019).

A total of 117 patients were recruited and their data were collected from paper or electronic medical records. HBV DNA and liver function were measured at baseline and throughout the 24-week follow-up. The effectiveness endpoint was complete virological response. The safety endpoint was the first occurrence of any clinical adverse event during the treatment.

Among the 117 patients, 45 had normal ALT as well as detectable HBV DNA and they were not recommended for antiviral therapy according to Chinese Guidelines (2019). After TAF antiviral therapy, the rates of patients who achieved HBV DNA <20 IU/mL at 4, 12 and 24 weeks were 77.1%, 96.7% and 96.8% respectively. Among them, the undetectable rates of HBV DNA in patients with low baseline viral load at 4, 12 and 24 weeks were 92.3%, 100% and 100%, while the rates of those with high baseline viral load were 68.2%, 94.1% and 94.4%. Compared with 71.4%, 94.4% and 94.7% in the high baseline group, the undetectable rates of HBV DNA at 4, 12 and 24 weeks in the low baseline liver stiffness group were 85.7%, 100% and 100%. There was no statistical significance among the above groups.

CHB patients who had normal ALT and detectable HBV DNA and did not meet “CHB prevention guide (2019)”, could achieve complete virological response in 24 weeks after antiviral treatment by TAF.

Change of gut microbiota composition is associated with the outcome of hepatitis B virus (HBV) infection, yet the related mechanisms are not fully characterized. The objective of this study was to investigate the immune mechanism associated with HBV persistence induced by gut microbiota dysbiosis.

C57BL/6 mice were sterilized for gut-microbiota by using an antibiotic (ABX) mixture protocol, and were monitored for their serum endotoxin (lipopolysaccharide [LPS]) levels. An HBV-replicating mouse model was established by performing HBV-expressing plasmid pAAV/HBV1.2 hydrodynamic injection (HDI) with or without LPS, and was monitored for serum hepatitis B surface antigen, hepatitis B e antigen, HBV DNA, and cytokine levels. Kupffer cells (KCs) were purified from antibiotic-treated mice and HBV-replicating mice and analyzed for IL-10 production and T cell suppression ability.

ABX treatment resulted in increased serum LPS levels in mice. The KCs separated from both ABX-treated and LPS-treated HBV-replicating mice showed significantly increased IL-10 production and enhanced ability to suppress IFN-γ production of TCR-activated T cells than the KCs separated from their counterpart controls. HDI of pAAV/HBV1.2 in combination with LPS in mice led to a delayed HBV clearance and early elevation of serum IL-10 levels compared to pAAV/HBV1.2 HDI alone. Moreover, IL-10 function blockade or KC depletion led to accelerated HBV clearance in LPS-treated HBV-replicating mice.

Our results suggest that dysbiosis of the gut microbiota in mice leads to endotoxemia, which induces KC IL-10 production and strengthens KC-mediated T cell suppression, and thus facilitates HBV persistence.

Yes-associated protein-1 (YAP1) is a potent transcriptional co-activator and functions as an important downstream effector of the Hippo signaling pathway, which is key to regulating cell proliferation, apoptosis, and organ growth. YAP1 has been implicated as an oncogene for various human cancers including gastrointestinal cancers and hepatocellular carcinoma (HCC). YAP1 promotes tumorigenesis and cancer progression by multiple mechanisms, such as by promoting malignant phenotypes, expanding cancer stem cells, and inducing epithelial-mesenchymal transition. YAP1 overexpression or its activated forms are associated with advanced pathological grades and poor prognosis of cancer, and therefore targeting YAP1 may open a fertile avenue for cancer therapy. In this review, we summarize the recent evidence regarding the role of YAP1 in the carcinogenesis of gastrointestinal cancers and HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and liver transplantation (LT) is the only potentially curative treatment. Over the years, Milan criteria has been used for patient selection. There is ongoing research in this field with introduction of new biomarkers for HCC that can help guide future treatment. Furthermore, newer therapies for downstaging of the tumor are being implemented to prevent dropout from the transplant list. In addition, combination therapies for better outcome are under investigation. Interestingly, the concept of living-donor LT and possible use of hepatitis C virus-positive donors has been implemented as an attempt to expand the organ pool. However, there is a conflict of opinion between different centers regarding its efficacy and data is scarce. The aim of this review article is to outline the various selection criteria for LT, discuss the outcomes of LT in HCC patients, and explore future directions of LT for HCC. Therefore, a comprehensive PubMed/MEDLINE review was conducted. To expand our search, references of the retrieved articles were also screened for additional data. After selecting the studies, the authors independently reviewed them to identify the relevant studies. After careful evaluation 120 studies relevant to out topic are cited in the manuscript. Three tables and two figures are also included. In conclusion LT for HCC has evolved over the years. With the introduction of several expanded criteria beyond Milan, the introduction of bridging therapies, such as transcatheter arterial chemoembolization and radiofrequency ablation, and the approval of newer systemic therapies, it is evident that there will be more LT recipients in the future. It is promising to see ongoing trials and the continuous evolution of protocols. Prospective studies are needed to guide the development of a pre-LT criteria that can ensure low HCC recurrence risk and is not overly stringent, clarify the role of LDLT, and determine the optimal bridging therapies to LT.

Fibroblast growth factor (FGF)19 has been implicated in the pathogenesis of murine hepatocellular carcinoma. Whether it plays a role in the development or course of human cholangiocarcinoma remains to be determined. The aim of this study was to determine whether prolonged exposure to FGF19 results in the transformation of non-malignant human cholangiocytes into cells with malignant features.

Human SV-40 transfected non-malignant H69 cholangiocytes were cultured with FGF19 (0-50 ng/mL) for 6 weeks, followed by 6 weeks with medium alone. Cell proliferation, invasion, stem cell surface markers, oncofetoprotein expression, state of differentiation, epithelial-mesenchymal transition (EMT) and interleukin (IL)-6 expression were documented at various time intervals throughout the 12-week period.

FGF19 exposure was associated with significant increases in cell proliferation, de-differentiation, EMT and IL-6 expression. However, each of these effects returned to baseline or control values during the 6-week FGF19 free follow-up period. The remaining cell properties remained unaltered.

Six weeks of FGF19 exposure did not result in the acquisition of permanent malignant features in non-malignant, human cholangiocytes.

Liver penetration by a confined perforation of peptic ulcer is a rare but severe event. Its clinical and pathological features are unclear.

In total, 41 qualified English publications were identified using the PubMed database and one in-house case.

Among the 42 patients, 20 patients had liver involvement by a perforated duodenal ulcer and 22 by a gastric ulcer. Among the 23 cases of known ulcer histology, 2 ulcers were malignant and were adenocarcinomas in the gastric remnant and the remaining 21 ulcers were confirmed as histologically benign (for frequency of malignancy in duodenal versus gastric ulcers, p = 0.48). The presence of hepatocytes was the clue of diagnosis for 19 cases. The median ages of the patients were 64.5 years (95% Confidence Intervals [CI] 53.40–71.90) for duodenal ulcer and 65.5 years (95% CI: 59.23–70.95) for gastric ulcer, respectively. The male to female ratio was 1.5:1 for duodenal ulcers and 2:1 for gastric ulcers. Patients with liver involvement of a perforated gastric ulcer were more likely to have a larger ulcer (median largest dimension, 4.75 cm versus 2.5 cm, p = 0.014). Female patients with liver involvement of a gastric ulcer were older than male patients (median age 72 versus 60 years, p = 0.045). There were no differences in gender, region (Asia, Europe, America versus others), use of non-steroidal anti-inflammatory drugs (n = 15), H. Pylori positivity (n = 10), possible history of peptic ulcer disease (n = 19) or mortality (n = 32) between duodenal and gastric ulcers.

Careful histologic examination, clinicopathological correlation, and immunohistochemistry are critical to establish the diagnosis and avoid misdiagnosing liver involvement as malignancy.

The coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality, prompting overwhelmed hospital systems to reallocate resources to those stricken with the disease. In response, many liver transplantation programs unexpectedly came to an abrupt halt, significantly affecting the lives of living donors and recipients around the world. As the risk-benefit scale of liver transplantation has changed in the era of COVID-19, it is prudent to understand the impact of COVID-19 on those with underlying liver disease and those in need of a liver transplant. In this review, we discuss recommendations put forth by hepatology and transplant societies, summarize results from emerging studies, and propose strategies to appropriately risk stratify patients prior to transplantation.

We present a unique case of biopsy-proven syphilitic hepatitis which presented as severe acute liver injury with significant elevation in aminotransferases and bilirubin, and improved with antibiotic therapy. However, the patient returned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia, positive autoantibody titers, and repeat liver biopsy demonstrating interface hepatitis, supporting a diagnosis of autoimmune hepatitis. He had an otherwise unrevealing etiologic workup, and responded to glucocorticoid therapy. We believe that syphilitic hepatitis and its treatment subsequently triggered an immunogenic response, leading to autoimmune hepatitis. Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults, especially hepatotropic pathogens. Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the development of autoantibodies. We propose that in the setting of syphilitic hepatitis, a molecular mimicry event resulting from structural similarities between T. pallidum and liver antigens, as well as impaired regulatory T-cell function, led to the breakdown of immune tolerance and the onset of autoimmune hepatitis. To support this hypothesis, further molecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis. Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease, as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell’s hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host’s innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85–99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.

Houttuynia cordata Thunb, which is a traditional Chinese herbal medicine, is commonly used as an anti-inflammatory, antiviral, and antibacterial agent in China. Emerging evidence shows that extracts of H. cordata Thunb have anticancer activity in human colorectal, leukemic, lung, and liver cancer cells; however, the specific active ingredients or compounds that responsible for these anticancer activities and their mechanism of action remain unknown. Sodium new houttuyfonate (SNH) is an additional product of the active ingredient houttuynin from H. cordata Thunb, which possesses anticancer activity; however, the molecular mechanisms that underlie its action have not been clarified. This study aims to explore the antitumor effect and related molecular mechanism of SNH on human non-small cell lung cancer (NSCLC).

The cytotoxicity of SNH against human lung cancer cells H1299 was investigated using WST-1 and apoptotic assays, and its antitumor molecular mechanism was explored using quantitative proteomics combined with various cellular and biochemical assays.

The results showed that SNH reduced the viability and enhanced the apoptosis of H1299 cells in a dose-dependent manner. Quantitative proteomics and ingenuity pathway analysis revealed that SNH downregulated the expression of cell cycle-related proteins, which included cyclin-dependent kinase 1 (CDK1), protein tyrosine phosphatase type IVA 2 (PTP4A2), and cyclin-dependent kinase 6 (CDK6), and upregulated the expression of Nrf2 (nuclear factor erythroid 2-related factor 2)-mediated oxidative stress response-related proteins in H1299 cells.

SNH-induced G0/G1 arrest and apoptosis in H1299 cells by the inhibition of cell cycle-related proteins that included CDK1, PTP4A2, CDK6, and activated the expression of Nrf2-mediated oxidative stress response-related proteins. These findings might provide new molecular mechanisms that underlie the antitumor activity of SNH against NSCLC and could implicate SNH as a novel therapeutic drug for NSCLC in the future.

Correct identification of small hepatocellular carcinomas (HCCs) and benign nodules in cirrhosis remains challenging, quantitative apparent diffusion coefficients (ADCs) have shown potential value in characterization of benign and malignant liver lesions. We aimed to explore the added value of ADCs in the identification of small (≤3 cm) HCCs and benign nodules categorized as Liver Imaging Reporting and Data System (LI-RADS) 3 (LR-3) and 4 (LR-4) in cirrhosis.

Ninety-seven cirrhosis patients with 109 small nodules (70 HCCs, 39 benign nodules) of LR-3 and 4 LR-4 based on major and ancillary magnetic resonance imaging features were included. Multiparametric quantitative ADCs of the lesions, including the mean ADC (ADCmean), minimum ADC (ADCmin), maximal ADC (ADCmax), ADC standard deviation (ADCstd), and mean ADC value ratio of lesion-to-liver parenchyma (ADCratio) were calculated. Regarding the joint diagnosis, a nomogram model was plotted using multivariate logistic regression analysis. The performance was assessed using the area under the receiver operating characteristic curve (AUC).

The ADCmean, ADCmin, ADCratio, and ADCstd were significantly associated with the identification of small HCC and benign nodules (p<0.001). For the joint diagnosis, the LI-RADS category (odds ratio [OR]=12.50), ADCmin (OR=0.14), and ADCratio (OR=0.12) were identified as independent factors for distinguishing HCCs from benign nodules. The joint nomogram model showed good calibration and discrimination, with a C-index of 0.947. Compared with the LI-RADS category alone, this nomogram model demonstrated a significant improvement in diagnostic performance, with AUC increasing from 0.820 to 0.967 (p=0.001).

The addition of quantitative ADCs could improve the identification of small HCC and benign nodules categorized as LR-3 and 4 LR-4 in patients with cirrhosis.

For high morbidity and mortality, hepatocellular carcinoma (HCC) becomes a major health issue worldwide. Nowadays, numerous non-coding RNAs (ncRNAs) are known to regulate the occurrence and pathogenesis of tumors. Some ncRNAs have also been developed as tumor biomarkers and therapeutic targets. However, the potential function of the small Cajal body-specific RNA (scaRNA) SCARNA16, a newly identified ncRNA, remains to be explored in HCC.

In both HCC cell lines and specimens from 120 enrolled patients, the expression values of SCARNA16 were detected. We divided patients into SCARNA16 high and low expression subgroups, and then analyzed the difference of various clinical characteristics and prognosis data between subgroups.

Compared to paired controls, SCARNA16 was significantly down-regulated in HCC cell lines and clinical specimens (p<0.01). Besides, HCC patients with lower SCARNA16 expression commonly presented with larger and more tumor lesions, more vessel carcinoma emboli, more capsular invasion and higher TNM stages (p<0.05). Moreover, SCARNA16 expression was negatively correlated with postoperative prognosis of HCC patients in 5-year follow-up, including tumor-free survival (TFS) (median time of low vs. high subgroups: 14 vs. 48 months, p=0.006) and overall survival (OS) (median time of low vs. high subgroups: 39 vs. 52 months, p=0.001). Besides, SCARNA16 acted as an independent prognostic biomarker in TFS (hazard ratio [HR]: 0.578, 95% CI: 0.345–0.969, p=0.038) and OS (HR: 0.366, 95% CI: 0.178–0.752, p=0.006).

Low expression patterns of SCARNA16 remarkably associated with severe clinical status and poor survival of patients, suggesting that SCARNA16 possesses potency as a novel biomarker for HCC.

B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.

Spontaneous bacterial peritonitis (SBP) is one of the leading causes of death in patients with liver cirrhosis. We aimed to establish a prognostic model to evaluate the 1-year survival of cirrhosis patients after the first episode of SBP.

A prognostic model was developed based on a retrospective derivation cohort of 309 cirrhosis patients with first-ever SBP and was validated in a separate validation cohort of 141 patients. We used Uno’s concordance, calibration curve, and decision curve (DCA) analysis to evaluate the discrimination, calibration, and clinical net benefit of the model.

A total of 59 (19.1%) patients in the derivation cohort and 42 (29.8%) patients in the validation cohort died over the course of 1 year. A prognostic model in nomogram form was developed with predictors including age [hazard ratio (HR): 1.25; 95% confidence interval (CI): 0.92–1.71], total serum bilirubin (HR: 1.66; 95% CI: 1.28–2.14), serum sodium (HR: 0.94; 95% CI: 0.90–0.98), history of hypertension (HR: 2.52; 95% CI: 1.44–4.41) and hepatic encephalopathy (HR: 2.06; 95% CI: 1.13–3.73). The nomogram had a higher concordance (0.79) compared with the model end-stage liver disease (0.67) or Child-Turcotte-Pugh (0.71) score. The nomogram also showed acceptable calibration (calibration slope, 1.12; Bier score, 0.15±0.21) and optimal clinical net benefit in the validation cohort.

This prediction model developed based on characteristics of first-ever SBP patients may benefit the prediction of patients’ 1-year survival.

Thioredoxin domain-containing 5 (TXNDC5) is an endoplasmic reticulum (ER) residing chaperon that is associated with the inflammatory phenotype of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs), such as high proliferation, cytokine production and invasion. However, if TXNDC5 is involved in communication between RA FLSs remains unknown.

Exosomes were separated and TXNDC5 expression in exosomes was detected by Western blotting, immunofluorescent staining, and flow cytometry. Cell Counting Kit-8 (CCK-8), Annexin V-APC/7-amino-actinomycin D staining, Western blotting, and enzyme-linked immuno sorbent assay (ELISA) were applied to detect the effects of exosomes on cell viability, apoptosis, activation of signaling pathways, and the production of inflammatory factors.

TXNDC5 protein was detected in the exosomes from RA FLSs and its content in exosomes increased when RA FLSs were stimulated by ER stress inducers. Functionally, TXNDC5 overexpressing RA FLSs-derived exosomes (TXNDC5-containing Exo) increased the production of inflammatory factors and the phosphorylated levels of extracellular regulated protein kinases (ERK), protein kinase B (PKB/Akt), p65 nuclear factor kappa beta (NF-κB), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in recipient FLSs. In addition, recipient FLSs with increased TXNDC5 expression were characterized by enhanced cell viability but a decrease in apoptosis in response to ER stress. More importantly, the introduction of TXNDC5-containing Exo protected recipient RA FLSs against the toxicity of methotrexate for viability, cytokine production, and apoptosis.

In combination, these results could provide a novel approach for TXNDC5 to communicate via exosomes between RA FLSs to exacerbate inflammation of RA and specific inhibition of exosome-mediated delivery of TXNDC5 has potential as a novel treatment strategy for RA.